Angiogenesis is the formation of new capillary blood vessels leading to neovascularization. Angiogenesis is a complex process which includes a series of sequential steps including endothelial cell-mediated degradation of vascular basement membrane and interstitial matrices, migration of endothelial cells, proliferation of endothelial cells, and formation of capillary loops by endothelial cells.
Both controlled and uncontrolled angiogenesis are thought to proceed in a similar manner. Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood vessels, then protrude through the basement membrane.
Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a “sprout” off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts merge with each other to form capillary loops, thereby creating the new blood vessel.
In normal physiological processes such as wound healing, angiogenesis is turned off once the process is completed. In contrast, tumor angiogenesis is not self-limiting. The progressive growth of solid tumors beyond clinically occult sizes (e.g., a few mm3) requires the continuous formation of new capillary blood vessels to deliver nutrients and oxygen for the tumor itself to grow, a process known as tumor angiogenesis. Solid tumors elicit an angiogenic response in the surrounding normal tissue for further growth. The resultant neovascularization of the tumor is associated with more rapid growth, and local invasion. Therefore, either inhibition of tumor angiogenesis (antiangiogenic therapy) or selective destruction of a tumor's existing blood vessels (vascular targeting therapy) would suppress or arrest tumor growth and its spread.
Further, in certain pathological (and nonmalignant) processes, angiogenesis is abnormally prolonged. Examples include ocular neovascular disease, which is characterized by invasion of new blood vessels into the retina or cornea, as well as other eye-related diseases. Other angiogenesis-associated diseases include diabetic retinopathy and chronic inflammatory diseases such as rheumatoid arthritis, dermatitis and atherosclerosis.
Antiangiogenic therapy has been proposed for modulating such angiogenesis-associated disorders. One approach has been to administer VEGF (vascular endothelial growth factor) inhibitors. Other approaches involve using angiostatin or endostatin, which are both known to inhibit angiogenesis. The in vivo use of angiostatin or endostatin is somewhat limited by their relatively short half-lives in vivo.
It would be advantageous to have new antiangiogenic compositions and methods to add to the arsenal of therapies available for treating these angiogenesis-mediated disorders. It would also be advantageous to have new methods for identifying such compositions and methods. The present invention provides such compositions and methods.